This invention relates to a new class of abscisic acid (ABA) analogs which have been altered at the 8'-or 9'-carbon atom, and to a novel process for synthesizing such ABA analogs.
1. Background
Abscisic acid is a plant hormone that regulates diverse aspects of plant growth including development and germination of seeds, transpiration, and responses to stress. ##STR2## abscisic acid, (+)-ABA (with numbering system for carbon atoms and conformation representation)
The hormone itself has found limited use as an externally applied plant growth regulator because of uptake and stability problems and because of cost.
Moreover, examination of the mechanisms of ABA action, identification of receptor proteins, and cellular localization of the hormone have been restricted by rapid turnover of the hormone in plants. Similarly, agricultural uses of applied ABA have been limited by rapid metabolism of the hormone in the plant.
In plants, the predominant pathway (see below) of metabolism of (+)-ABA involves hydroxylation at the 8' position affording 8'-hydroxyABA (2) which undergoes cyclization by attack of the 8'-hydroxyl group onto the enone system producing phaseic acid (PA, 3). The intermediate hydroxylated ABA compound 2 has rarely been found in plant extracts, most probably because it readily cyclizes during manipulation. Phaseic acid (3) the more readily isolable ABA catabolite, has little or no activity in most assays. ##STR3##
2. Description of the Prior Art
Recently, new ABA analogs bearing a methoxy group on either the 8' or 9'-carbon atom have been synthesized and tested by Hirai's group in Japan (Y. Todokori, N. Hirai and K. Koshimuzuz. 8' and 9'-methoxyabscisic acids as antimetabolic analogs of abscisic acid Biosci. Biotech. Biochem 1994 58: 707-715); S. Nakano, Y. Todoroki, N. Hirai, and H. Ohigashi. Synthesis and biological activity of 7'-, 8'- and 9'-alkyl analogizes of abscisic acid Biosci. Biotech. Biochem. 1995 59 699-1706). These compounds were found to have potent activity, depending upon the assay. Their results suggest that modifying the geminal dimethyl groups in some instances does not prevent the molecule from being perceived as ABA-like, and the authors postulate that the alterations prevent rapid metabolic breakdown by enzymes that degrade ABA.
However, the syntheses that they used are not practical. Their procedure for the methoxy derivatives takes 15 steps, with one reaction that gives a mixture of double bond isomers, and another that gives a mixture of diastereomers at the 1' and 6'- carbons. The yield of racemic methyl ethers, as a mixture with the trans forms, i.e. four compounds, is calculated from their experimental results to be 0.22%. The alkyl analogs are synthesized by similar routes and overall poor efficiency.
Two groups have synthesized 8'-fluorinated ABA analogs that have potent biological activity (Y. Todoroki, N. Hirai, K. Koshimizu. 8', 8' difluoro- and 8',8', 8'- trifluroabscisic acids as highly potent long lasting analogues of abscisic acid Phytochem. 1995 38: 561-568. B. T. Kim, Y. K. Min, T. Asami, N. K Park, I. H. Jeong, K. Y. Cho and S. Yoshida. Synthesis and biological activities of new fluorinated abscisic acid. Bioorganic and Medicinal Chem. Lett. 1995 5 275-278). In both cases the syntheses are lengthy and not practical for plant growth regulator applications.